Intraocular drug delivery device and associated methods

ABSTRACT

An intraocular active agent delivery device can include an active agent homogenously combined with a biodegradable active agent matrix such that the entire delivery device is homogenous. The homogenous delivery device can have a shape and size to fit within a lens capsule or ciliary sulcus of an eye and provide a therapeutically effective amount of the active agent to the eye. The biodegradable active agent matrix can be formulated to provide sustained release of the therapeutically effective amount of the active agent during a release period. In some examples, the active agent can include dexamethasone.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/590,868, filed on May 9, 2017 which is a continuation-in-part of U.S.application Ser. No. 15/391,666, filed Dec. 27, 2016, which is acontinuation-in-part of U.S. application Ser. No. 13/543,597, filed Jul.6, 2012, which is a continuation-in-part of U.S. application Ser. No.13/211,169, filed Aug. 16, 2011 and now issued as U.S. Pat. No.9,095,404, which is a continuation-in-part of U.S. application Ser. No.12/945,428, filed Nov. 12, 2010 and now issued as U.S. Pat. No.8,663,194, which is a continuation-in-part of International ApplicationNo. PCT/US2009/043566, filed May 12, 2009, which claims priority to U.S.Provisional Application No. 61/052,507, filed May 12, 2008, which areeach incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to systems, methods, and devices for thesustained and targeted (local) delivery of a pharmaceutical active agentinto a subject's eye. Accordingly, the present invention involves thefields of polymer chemistry, material science, polymer science, drugdelivery, formulation science, pharmaceutical sciences, and medicine,particularly ophthalmology.

BACKGROUND

Age-related macular degeneration (AMD) and glaucoma are two of theleading causes of blindness in the United States and across the world.Present glaucoma therapies generally require polypharmacy, wheresubjects are often prescribed several topical agents that must beapplied to the eye with varying frequencies, in some cases up to 3 or 4times a day. These dosing regimens are often difficult for subjects toconsistently follow, and many individuals progress to needing surgicaltreatments such as intraocular shunts or trabeculectomies, which havesignificant attendant complications.

Subjects having macular degeneration are often required to have monthlyintravitreal injections. Such injections are painful and may lead toretinal detachment, endophthalmitis, and other complications.Furthermore, these injections are generally performed only by retinalsurgeons, a small fraction of the ophthalmic community, producing abottleneck in eye care delivery and increased expense.

Postoperative surgery inflammation is associated with raise intraocularpressure (TOP), and increase the likelihood of cystoid macular edema(CME), synechial formation, posterior capsule opacification (PCO), andsecondary glaucoma. Patient compliance is of concern in the managementof postoperative inflammation because multiple eye drops must be takenmultiple times per day at regular intervals over the course of weeks.Poor compliance compromises the efficacy of topical drugs, which arefurther limited by corneal absorption and have highly variableintraocular concentrations during the therapeutic course. Uveitisspecifically refers to inflammation of the middle layer of the eye,termed the “uvea” but in common usage may refer to any inflammatoryprocess involving the interior of the eye. Uveitis is estimated to beresponsible for approximately 10% of the blindness in the United States.

Postoperative cataract surgery inflammation can be well controlled byimproving patient compliance. Available literature and experience showspenetration of the drug after topical administration is poor and highersystemic concentration means frequent systemic adverse events. All ofthese factors highlight the need for sustained intraocular delivery forpharmaceutical active agents to effectively control inflammation.

SUMMARY

An intraocular active agent delivery device can include an active agenthomogenously combined with a biodegradable active agent matrix such thatthe entire delivery device is homogenous. The homogenous delivery devicecan have a shape and size to fit within a lens capsule or ciliary sulcusof an eye and provide a therapeutically effective amount of the activeagent to the eye. The biodegradable active agent matrix can beformulated to provide sustained release of the therapeutically effectiveamount of the active agent during a release period. In some examples,the active agent can include dexamethasone.

A method of treating an eye condition can include inserting anintraocular active agent delivery device into the lens capsule orciliary sulcus of an eye. The intraocular active agent delivery devicecan include an active agent homogenously combined with a biodegradableactive agent matrix such that the entire delivery device is homogenous.The homogenous delivery device can have a shape and size to provide atherapeutically effective amount of the active agent to the eye. Thebiodegradable active agent matrix can be formulated to provide sustainedrelease of the therapeutically effective amount of the active agentduring a release period. In some examples, the active agent can includedexamethasone. The method can further include allowing the biodegradableactive agent matrix to biodegrade to provide sustained release of thetherapeutically effective amount of the active agent to the eye duringthe release period.

There has thus been outlined, rather broadly, the more importantfeatures of the invention so that the detailed description thereof thatfollows may be better understood, and so that the present contributionto the art may be better appreciated. Other features of the presentinvention will become clearer from the following detailed description ofthe invention, taken with the accompanying drawings and claims, or maybe learned by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph showing a bioerodible dexamethasone implant(BDI), in accordance with some examples of the present disclosure.

FIG. 2 is a bar graph showing the amount of an active agent present invarious eye tissues following implantation of an intraocular device inaccordance with a further aspect of the present invention.

FIG. 3 is a graph of in-vitro release kinetics of an example BDIimplant. Data are presented as mean±SD (n=3).

FIG. 4 time vs concentration profile of an example BDI implant with 120to 160 μg of dexamethasone (DXM) in aqueous and vitreous humor of NewZealand White (NZW) rabbits.

FIG. 5 time vs concentration profile of an example BDI implant with 120to 160 μg of DXM in iris/ciliary body and retina/choroid of NZW rabbits.

FIG. 6 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in aqueous humor of New Zealand white rabbits.

FIG. 7 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in vitreous humor of New Zealand whiterabbits.

FIG. 8 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in retina/choroid of New Zealand whiterabbits.

FIG. 9 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in iris/ciliary body of New Zealand whiterabbits.

FIG. 10 is a graph illustrating the effect of croscarmelloseconcentration on drug release for some example BDI implants.

FIG. 11 is a graph of in-vitro release kinetics of an example BDIimplant. Data are presented as mean±SD (n=3).

FIG. 12 is a graph of in-vitro release kinetics of another example BDIimplant. Data are presented as mean±SD (n=3).

FIG. 13 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in aqueous humor of New Zealand white rabbits.

FIG. 14 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in vitreous humor of New Zealand whiterabbits.

FIG. 15 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in retina/choroid of New Zealand whiterabbits.

FIG. 16 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in iris/ciliary body of New Zealand whiterabbits.

FIG. 17 is a graph of retinal thickness vs. time profile of an exampleBDI implant and topical drops as compared to normal control.

FIG. 18 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in aqueous humor of New Zealand white rabbits.

FIG. 19 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in vitreous humor of New Zealand whiterabbits.

FIG. 20 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in retina/choroid of New Zealand whiterabbits.

FIG. 21 is a graph of time vs. concentration profile of an example BDIimplant and topical drops in iris/ciliary body of New Zealand whiterabbits.

FIG. 22 is a graph of retinal thickness vs. time profile of an exampleBDI implant and topical drops as compared to normal control. Thesedrawings merely depict exemplary embodiments of the present inventionand they are, therefore, not to be considered limiting of its scope. Itwill be readily appreciated that the components of the presentinvention, as generally described and illustrated in the figures herein,could be arranged, sized, and designed in a wide variety of differentconfigurations.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of exemplary embodiments of theinvention makes reference to the accompanying drawings, which form apart hereof and in which are shown, by way of illustration, exemplaryembodiments in which the invention may be practiced. While theseexemplary embodiments are described in sufficient detail to enable thoseskilled in the art to practice the invention, it should be understoodthat other embodiments may be realized and that various changes to theinvention may be made without departing from the spirit and scope of thepresent invention. Thus, the following more detailed description of theembodiments of the present invention is not intended to limit the scopeof the invention, as claimed, but is presented for purposes ofillustration only and not limitation to describe the features andcharacteristics of the present invention, to set forth the best mode ofoperation of the invention, and to sufficiently enable one skilled inthe art to practice the invention. Accordingly, the scope of the presentinvention is to be defined solely by the appended claims.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a drug” includes reference to one or more of such drugs,“an excipient” includes reference to one or more of such excipients, and“filling” refers to one or more of such steps.

Definitions

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

As used herein, “active agent,” “bioactive agent,” “pharmaceuticallyactive agent,” and “drug,” may be used interchangeably to refer to anagent or substance that has measurable specified or selected physiologicactivity when administered to a subject in a significant or effectiveamount. These terms of art are well-known in the pharmaceutical andmedicinal arts.

As used herein, “formulation” and “composition” may be usedinterchangeably herein, and refer to a combination of two or moreelements, or substances. In some embodiments a composition can includean active agent, an excipient, or a carrier to enhance delivery, depotformation, etc.

As used herein, “effective amount” refers to an amount of an ingredientwhich, when included in a composition, is sufficient to achieve anintended compositional or physiological effect. Thus, a “therapeuticallyeffective amount” refers to a substantially non-toxic, but sufficientamount of an active agent, to achieve therapeutic results in treating orpreventing a condition for which the active agent is known to beeffective. It is understood that various biological factors may affectthe ability of a substance to perform its intended task. Therefore, an“effective amount” or a “therapeutically effective amount” may bedependent in some instances on such biological factors. Further, whilethe achievement of therapeutic effects may be measured by a physician orother qualified medical personnel using evaluations known in the art, itis recognized that individual variation and response to treatments maymake the achievement of therapeutic effects a subjective decision.However, the determination of an effective amount is well within theordinary skill in the art of pharmaceutical and nutritional sciences aswell as medicine.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a composition or method as recited herein. Examples ofsubjects include humans, and can also include other animals such ashorses, pigs, cattle, dogs, cats, rabbits, aquatic mammals, etc.

As used herein, the term “intraocular lens” refers to a lens that isutilized to replace a lens in the eye of a subject. Such intraocularlenses can be synthetic or biological in nature. Furthermore, in someaspects the term “intraocular lens” can also refer to the originalnatural lens that is associated with the eye.

As used herein, the term “ciliary sulcus” refers to the space betweenthe posterior root of the iris and the ciliary body of the eye.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result. For example, an object that is“substantially” enclosed would mean that the object is either completelyenclosed or nearly completely enclosed. The exact allowable degree ofdeviation from absolute completeness may in some cases depend on thespecific context. However, generally speaking the nearness of completionwill be so as to have the same overall result as if absolute and totalcompletion were obtained. The use of “substantially” is equallyapplicable when used in a negative connotation to refer to the completeor near complete lack of an action, characteristic, property, state,structure, item, or result. For example, a composition that is“substantially free of” particles would either completely lackparticles, or so nearly completely lack particles that the relevanteffect would be the same as if it completely lacked particles. In otherwords, a composition that is “substantially free of” an ingredient orelement may still actually contain such item as long as there is nomeasurable effect thereof.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

As used herein, the term “at least one of” is intended to be synonymouswith “one or more of” For example, “at least one of A, B and C”explicitly includes only A, only B, only C, and combinations of each.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 1 to about 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4,and from 3-5, etc. This same principle applies to ranges reciting onlyone numerical value. Furthermore, such an interpretation should applyregardless of the breadth of the range or the characteristics beingdescribed.

Any steps recited in any method or process claims may be executed in anyorder and are not limited to the order presented in the claims unlessotherwise stated. Means-plus-function or step-plus-function limitationswill only be employed where for a specific claim limitation all of thefollowing conditions are present in that limitation: a) “means for” or“step for” is expressly recited; and b) a corresponding function isexpressly recited. The structure, material or acts that support themeans-plus function are expressly recited in the description herein.Accordingly, the scope of the invention should be determined solely bythe appended claims and their legal equivalents, rather than by thedescriptions and examples given herein.

Intraocular Drug Delivery Device

An intraocular drug delivery device can provide improved ophthalmic drugdelivery by alleviating the need for multiple injections or complexeyedrop regimens by providing an intra-capsular homogeneous matrixreservoir which is implantable and biodegrades such that subsequentsurgery is often unnecessary. Further, the device can deliver a varietyor combination of different medicines.

A novel intraocular drug delivery device, system, and associated methodsfor providing sustained release of ocular active agents for extendedperiods of time are disclosed and described. One problem with many eyediseases, such as Age-related Macular Degeneration (AMD), is theconstant need for a subject to receive painful ocular injections, whichhave significant risks of retinal detachment, vitreous hemorrhage, andendophthalmitis. The intraocular drug delivery device allows forsustained release of an active agent over time, thus eliminating theneed for frequent ocular injections.

It should be noted that neovascularization is a key pathobiologicalprocess in a variety of eye diseases, such as AMD, proliferativediabetic retinopathy, vascular occlusive disease, and radiationretinopathy. Additionally, the incidence of glaucoma is increasingworldwide. Many other disorders, including severe uveitis and geographicatrophy in AMD, can be treated using such an intraocular drug deliverydevice. Thus, an implantable, generally sutureless drug delivery devicefor placement in the anterior segment of the eye has great potential toimprove the quality of life for subjects.

The drug delivery device can continuously deliver dexamethasone or otheranti-inflammatory or therapeutic agents with near zero order kineticsfor two weeks or more. Treatment of uveitis needs long term (6-8 weeks)sustained delivery of anti-inflammatory agents. The biggest disadvantagewith topical drops is that negligible concentrations of drugs will reachthe posterior segment of the eye and especially the retina/choroid. Thedesigned and disclosed drug delivery device can deliver dexamethasoneand/or other therapeutic agents continuously with near zero orderkinetics both to the anterior and posterior segments of the eye, thuseffectively controlling the inflammation.

It some instances it is desirable to have a burst effect of drug overthe 24 or 48 hours followed by a near zero order delivery kineticssubsequent to the initial 24 to 48 hours. In some cases, the burst candeliver up to 10, 20, or up to 30% with in the first day or two while inother cases it can be desirable to have no burst effect where less than5% of the drug is delivered in the first day or two. In the case ofsteroid delivery a burst effect may be advantageous to more closelymimic the dosing regimens. The use of croscarmellose and otherdisintegrants and/or super-disintegrants controls how much drug isreleased in the first day or two. As a general guideline, an amount ofdisintegrant can range from 0 to 20 wt % of the matrix. Furthermore,annealing conditions during manufacturing and storage conditions aftermanufacturing can also aid in controlling the burst affect. For example,storage and implant temperature maintained near ambient temperature canincrease initial burst delivery, while cooler temperatures such as 2 to8° C. can decrease initial burst delivery. Similarly, annealing of thedevice can decrease the burst effect. For example, annealing at ananneal temperature from 50 to 90° C. (and in some cases 60 to 80° C.)for 15 to 45 minutes can markedly reduce burst effect. Thus, the bursteffect can be varied or eliminated based on a desired therapeutic effectand delivery profile.

Therefore, the opportunity exists to improve management of AMD,postoperative surgery inflammation, and uveitis patients undergoingcataract surgery by sustained release of pharmaceutical active agent(s).Accordingly, the present invention provides systems, devices, andassociated methods for the delivery of active agents into the eye of asubject. In some examples, the systems, devices, and associated methodscan be positioned within the anterior segment of the eye (e.g. withinthe lens capsule) of a subject to deliver an active agent to theposterior segment of an eye of the subject. Non-limiting examples ofocular regions found within the posterior segment of the eye can includeat least one of the vitreous humor, the choroid, and the retina. Inaddition to delivering the active agent to the posterior segment of theeye, the active agent can also be delivered to the anterior segment ofthe eye. The anterior segment of the eye can include at least one of theaqueous humor, the iris, and the lens capsule. In one aspect, theintraocular device can be sutureless. A sutureless device can be definedas a device or structure that can be inserted and retained within a lenscapsule without the need for a suture to hold the device in place.

In further detail, in some aspects, the device can be implantable withinthe lens capsule (e.g. after removal of a native lens) during cataractsurgery, essentially “piggybacking” on the cataract extraction, and thuseliminating the need for additional surgical procedures. One benefit to“piggybacking” on the cataract extraction is the ability to deliversteroids, antibiotics, and/or various non-steroidal agents directly tothe eye after surgery, thus helping to minimize complications such ascystoid macular edema.

In other aspects, the device can be implanted in a surgery that isseparate from a cataract procedure, e.g., subsequent to a previouscataract extraction with reopening of the lens capsule. For example, thedevice can be implanted post-cataract surgery for treatment of maculardegeneration, retinal vein or artery occlusion, diabetic retinopathy,macular edema (e.g. from diabetes, uveitis, intraocular surgery, etc.),retinal degenerations where a neuroprotectant delivery is indicated, orthe like.

In one embodiment, the device can be provided in the form of an implantcontaining an active agent within a biodegradable or bioerodible polymermatrix. The biodegradable active agent matrix can include an activeagent in an amount to deliver a therapeutically effective amount ortherapeutically effective dose of the active agent to the posteriorsegment of the eye from the lens capsule. A therapeutically effectiveamount or therapeutically effective dose can vary depending on theparticular therapeutic agent being employed in the biodegradable activeagent matrix. Further, the therapeutically effective amount ortherapeutically effective dose can vary depending on the severity of thecondition being treated. Nonetheless, the active agent can be present inan amount to facilitate delivery of the active agent from the anteriorsegment of the eye (e.g. from the lens capsule) to the posterior segmentof the eye.

The therapeutically effective amount or therapeutically effective dosecan typically range from about 50 micrograms (mcg) to about 10milligrams (mg), depending on the active agent being employed and theseverity of the condition. In some specific examples, thetherapeutically effective amount or therapeutically effective dose canrange from about 50 mcg to about 600 mcg. In yet other examples, thetherapeutically effective amount or therapeutically effective dose canrange from about 100 mcg to about 400 mcg, from about 100 mcg to about300 mcg, or from about 200 mcg to about 400 mcg. In yet further detail,the active agent can typically be present in the implant at aconcentration of from about 5 wt % to about 25 wt %, or from about 5 wt% to about 15 wt %, or from about 10 wt % to about 20 wt %, although upto about 50 wt % can be useful in some applications. Further still,depending on the dosage requirements, one, two or more implants can beimplanted per eye to achieve a therapeutically effective dose.

The biodegradable active agent matrix can be configured to bioerode toprovide controlled release of the therapeutically effective amount overa period of days, weeks, or months. In some examples, thetherapeutically effective amount can be released over a period rangingfrom about 1 week to about 10 weeks. In other examples, thetherapeutically effective amount can be released over a period rangingfrom about 1 week to about 3 weeks, from about 2 weeks to about 6 weeks,or from about 5 weeks to about 8 weeks. In cases such as retinalvein/artery occlusion, diabetic retinopathy, macular edema or retinaldegenerations, the period can often range from 2 months to 12 months,and in some cases from 2.5 months to 5 months. For example, bioerodiblelipid polymers and/or bioerodible polycaprolactone can be used as anextended release matrix material.

Thus, in some examples, the delivery device can release from about 50mcg to about 10 mg of active agent over a period of from about 1 week toabout 12 months. In some additional examples, the delivery device canrelease from about 50 mcg to about 600 mcg of active agent over a periodof from about 1 week to about 10 weeks. In yet other examples, thedelivery device can release from about 100 mcg to about 400 mcg ofactive agent over a period of from about 2 weeks to about 8 weeks. Instill other examples, the delivery device can release from about 100 mcgto about 300 mcg, or from about 200 mcg to about 400 mcg of active agentover a period of from about 2 weeks to about 8 weeks. In two specificexamples, the delivery device can release 200 mcg over 2-3 weeks or 300mcg over 6-8 weeks.

In some specific examples, the delivery device can deliver an average offrom about 0.5 mcg to about 90 mcg per day of the active agent during arelease period, and in some cases up to about 30 mcg per day. In otherexamples, the delivery device can deliver an average of from about 1 mcgto about 12 mcg per day of the active agent during a release period. Inyet other examples, the delivery device can deliver an average of fromabout 2 mcg to about 8 mcg per day of the active agent during a releaseperiod.

It is noted that in addition to the amount of the active agent presentin the biodegradable active agent matrix, other additional factors canaffect the delivery of the active agent to the posterior segment of theeye. For example, the intracapsular positioning of the device within thelens capsule can affect delivery of the active agent to the posteriorsegment of the eye. In some examples, positioning of the implant at alocation inferior and peripheral to the intraocular lens (IOL) or withinthe inferior peripheral capsule can provide suitable delivery of theactive agent to the posterior segment of the eye. Typically, the implantcan also be located at a lower portion within the lens capsule. Forexample, the implant can be oriented within the inferior periphery,annular periphery encircling the intraocular lens for at least 180degrees, or the like as long as a line of sight is not obstructed.

Further still, the molecular weight and molecular size of the activeagent can affect delivery of the active agent to the posterior segmentof the eye. Thus, in some examples, the active agent can have amolecular weight of 250,000 daltons (Da) or less. In yet other examples,the active agent can have a molecular weight of 170,000 Da or less. Inyet additional examples, the active agent can have a molecular weight of500 Da or less.

Numerous active agents are known for the treatment or prophylaxis ofvarious eye conditions, such as AMD (neovascular form or atrophic form),glaucoma, diabetic retinopathy, Retinopathy of Prematurity, uveitis,corneal transplant rejection, capsular fibrosis, posterior capsuleopacification, retinal vein occlusions, infections, and the like. Anysuitable active agent for incorporation into a biodegradable activeagent matrix can be used, such as steroids, NSAIDs, antibiotics,anti-VEGF agents, PDGF-B inhibitors (Fovista®), integrin antagonists,complement antagonists, the like, or combinations thereof. Non-limitingexamples of suitable active agents can include dexamethasone,prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis®),sunitinib, pegaptanib (Macugen®), moxifloxacin, gatifloxicin,besifloxacin, timolol, latanoprost, brimonidine, nepafenac, bromfenac,diclofenac, ketorolac, triamcinolone, difluprednate, fluocinolide,aflibercept, the like, or combinations thereof. Treatment regimens canadditionally include various photodynamic therapies, and the like. Inone specific example, the active agent can include dexamethasone.

The bioerodible polymer matrix can include one or several excipients,which can depend on the duration of active agent delivery. Non-limitingexamples of active agent matrix materials can include polymeric andnon-polymeric materials. Specific non-limiting examples of suitablematrix materials include biodegradable polymers such as PLGA (differentratios of lactic to glycolide content and end groups such as acid orester termination), PVA, PEG, PLA, PGA, hydroxypropylcellulose, sodiumcarboxymethylcellulose, croscarmellose sodium, polycaprolactone,hyaluronic acid, albumin, sodium chloride block copolymers thereof, andthe like. Specific copolymers such as polylactic-polyglycolic acid blockcopolymers (PLGA), polyglycolic acid-polyvinyl alcohol block copolymers(PGA/PVA), hydroxypropylmethylcellulose (HPMC),polycaprolactone-polyethylene glycol block copolymers, croscarmellose,and the like can be particularly effective. In one aspect, the activeagent matrix can be a PLGA having about 45-80% PLA and 55-20% PGA suchas about 65% PLA and 35% PGA, and in one case about 50% PLA and 50% PGA.In another alternative embodiment, the weight ratios of PLGA,dexamethasone, and Croscarmellose sodium can be 60-90/5-25/5-25 or50-75/10-40/10-40 ratios. In another aspect, the biodegradable activeagent matrix comprises a low melt fatty acid such as, but not limitedto, lauric acid, myrisitic acid, palmitic acid, stearic acid, arachidicacid, capric acid, oleic acid, palmitoleic acid, and mixtures thereof.In one aspect, the biodegradable active agent matrix can comprise apharmaceutically acceptable disintegrant. In one example, thedistintegrant can be a superdistintegrant. Non-limiting examples ofsuitable disintigrants include crosslinked celluloses (e.g.croscarmellose, Ac-Di-Sol, NYMCE ZSX, PRIMELLOSE, SOLUTAB, VIVASOL),microcrystalline cellulose, alginates, crosslinked PVP (e.g.CROSSPOVIDONE, KOLLIDON, POLYPLASDONE), crosslinked starch, soypolysaccharides, calcium silicate, salts thereof, and the like. In oneexample, a disintigrant can include croscarmellose from 3 wt % to 25 wt%, and in one case from 3 wt % to 20 wt % of the active agent matrix.Croscarmellose at greater than about 25 wt % can be useful for deliverytimes less than about 1 week, while less than about 3% can be useful forextended delivery times of greater than 6 to 9 months.

Typically, the delivery device herein can be targeted for a relativelyshort delivery duration, such as less than eight weeks. In someexamples, the active agent has a delivery duration of from about twoweeks to about six or eight weeks. Delivery duration can be a functionof the type of polymer used in the matrix, copolymer ratios, and otherfactors. Although other biodegradable polymers can be suitable such asthose listed previously, particularly suitable polymers can include atleast one of poly(lactic-co-glycolide), hydroxypropyl methyl cellulose,hydroxyl methyl cellulose, polyglycolide-polyvinyl alcohol,croscarmellose, polycaprolactone, eudragit L100, eudragit RS100,poly(ethylene glycol) 4000, poly(ethylene glycol) 8000 and poly(ethyleneglycol) 20,000. In one example, the biodegradable active agent matrixcan comprise poly(lactic-co-glycolide) having a copolymer ratio from10/90 to 90/10 and in another case from 52/48 to 90/10. In yet otherexamples, the copolymer ratio can be from about 60/40 to about 40/60, orfrom about 55/45 to about 45/55. One particular aspect, the copolymerratio can be about 50/50. In another specific example, the copolymerratio can be 52-78/48-22 and in another specific example from60-90/40-10. Although degradation rates can be dependent on suchproportions, additional alternative approaches can also be useful suchas device coatings, particle encapsulation, and the like.

Homogeneous delivery devices can be formed, for example, by mixing apolymer material with a loading amount of active agent to form a matrixdispersion or solution. The active agent can be homogeneously dispersedas a solid, dissolved uniformly, or partially dissolved as long asuniformity and homogeneity is maintained. Thus, in some examples, theactive agent can be homogenously combined with the matrix such that theentire delivery device is homogenous or substantially homogenous. Morespecifically, the homogeneity can extend throughout the entire devicesuch that the device consists essentially of the homogeneously mixedmatrix and active agent along with optional additives. The loadingamount can be chosen to correspond to the desired dosage duringdiffusion. Loading amount can take into account diffusioncharacteristics of the polymer and active agent, residual active agent,delivery time, and the like. The matrix dispersion can then be formedinto the device shape using any suitable technique. For example, thematrix dispersion can be cast, sprayed and dried, extruded, stamped, orthe like. Such configurations will most often be formed using abiodegradable matrix, although non-biodegradable materials can also beused. In one alternative formulation, the device can be formed in situfrom a suspension of the active agent within a biodegradable polymermatrix precursor. Upon delivery into the target site, the biodegradablepolymer matrix precursor can form (via precipitation and/orpolymerization) the biodegradable active agent matrix in situ.

It is noted that with homogenous delivery devices, the shape and size ofthe delivery device can play an important role in the amount and rate ofdelivery of the active agent. For example, where a biodegradable activeagent matrix is employed in the homogenous delivery device, thebiodegradable matrix can generally accommodate various levels of activeagent while maintaining a desirable biodegradation profile. Theparticular amount of active agent that a biodegradable matrix cancontrollably release within a particular biodegradation profile candepend on both the composition of the biodegradable matrix and theparticular active agent being employed. Thus, in some examples, theparticular composition of the homogenous delivery device can be somewhatconstrained for a particular biodegradation profile and active agentcombination.

Accordingly, the overall shape and size of the homogenous deliverydevice can be manipulated to accommodate faster and slower release ratesand greater or smaller amounts of overall active agent released by thehomogenous delivery device while maintaining suitable compositionalparameters for a desired release profile. For example, in some cases, alarge amount of a particular active agent can be required to provide atherapeutically effective amount to a subject to treat a particularcondition. In such examples, the overall size of the homogenous deliverydevice can be increased to accommodate the large amount of active agent.Conversely, the overall size of the homogenous delivery device can bereduced where lesser amounts of the active agent are needed.

However, it is noted that, in some examples, increasing the size of thehomogenous delivery device can also obstruct a line of sight in the eye.Thus, in some examples, the overall shape of the device can bemanipulated to prevent obstruction of a line of sight in the eye. Forexample, in some cases, the homogenous delivery device can have acrescent shape, an ellipsoid shape (e.g. a disc shape, a football shape,an egg shape, or the like), a rod shape, or the like, to allow the sizeto increase to a greater extent along one axis relative to aperpendicular axis so as to not obstruct a line of sight in the eye.

Further, the shape of the homogenous delivery device can also affect theactive agent release rate for the homogenous delivery device. Forexample, in some cases, a thinner homogenous delivery device canbiodegrade more quickly than a thicker homogenous delivery device,resulting in a faster active agent release profile. Additionally, insome examples, the perimeter edges or other sections of the homogenousdelivery device can be made thinner and/or rougher than other parts ofthe homogenous delivery device to provide an initial burst of activeagent followed by a near zero order release profile. Further, in someexamples, the overall geometrical shape alone of the homogenous deliverydevice can affect the release rate of the active agent. For example,exposed surface area to volume ratio can be increased to increaserelease rate and degradation.

With the above homogeneous delivery device, particular efficacy can beprovided for treatment of uveitis and post-operative cataract surgeryinflammation. For example, dexamethasone can be dispersed within abiodegradable active agent matrix. Although dexamethasone dosage amountscan vary, generally from about 100 mcg to about 400 mcg can be effectivefor these indications. More specifically, some patients may becategorized as low risk while others can be categorized as high risk dueto various factors such as age, secondary complications, pre-existingconditions, etc. Most often, a low risk patient can benefit from a lowdosage of about 100 mcg to about 150 mcg. In contrast, a high riskindividual can be administered a high dosage of about 250 mcg to about350 mcg. Some biodegradable implants can specifically designed andtested for the treatment of postoperative surgery inflammation and candeliver pharmaceutical active agent up to or about 2 weeks or more. Yetother biodegradable implants can be designed and tested for thetreatment of postoperative surgery inflammation and uveitis and candeliver active agent up to or about 6-8 weeks or more. Further,depending on the severity of the inflammation, one, two, more implantscan be implanted per eye during surgery.

The active agent delivery devices can optionally include additionalactive agents or other desired therapeutically beneficial substances. Inone aspect, for example, the device can include at least one secondaryactive agent. Where a plurality of active agents is included in theactive agent delivery device, the active agent matrix can be homogenousor non-homogenous. In some examples, the active agent delivery devicecan include a plurality of active agents and can be homogenous. In someexamples, the active agent delivery device can include a plurality ofactive agents and can be non-homogenous. For example, one active agentcan be coated on the surface of the implant. In yet other examples, theimplant can be formulated to have pre-designated regions or layersincluding different active agents. In yet other examples, the implantcan be formulated to have pre-designated regions or layers having thesame active agent, but at different concentrations. For example, in somecases, an outer region or layer of the implant can have a higherconcentration of the active agent to deliver a higher initial dose orburst of the active agent followed by a prolonged lower dose over aperiod of days or weeks. Further, in some examples, different regions ofthe implant can be adapted to biodegrade at different rates. In yetother examples, agents can optionally be coated on the implant to reducethe incidence of capsular fibrosis. Non-limiting examples of such agentsinclude anti-cell proliferative agents, anti-TGF-beta agents, a5b1integrin antagonists, rapamycin, and the like.

The ocular active agent delivery device can be configured to fit withina lens capsule or ciliary sulcus of an eye. The delivery device can beshaped in any geometry which allows for insertion into the lens capsuleor ciliary sulcus. For example, the implant can be in the shape ofround, square shape, crescent, or donut shape. However, other suitableshapes can include, but are not limited to, discs, pellets, rods, andthe like. Although dimensions can vary, typical dimensions can rangefrom about 0.5 mm to about 4 mm width and about 0.2 mm to about 1 mmthickness. Although the total mass of the delivery device can vary, mostoften the total mass can be from 0.2 mg to 4 mg, or from about 1.5 mg toabout 2.5 mg. For example, about 2 mg total mass can provide effectiveactive agent volume, while also balancing overall size to fit within thetarget tissue areas.

In some specific examples, the implant can be shaped as a disc orpellet. Where this is the case, the implant can typically have adiameter ranging from about 0.4 millimeters (mm) to about 3 mm, fromabout 0.5 mm to about 1.5 mm, or from about 0.7 mm to about 1.3 mm.Further, in some examples, the disc- or pellet-shaped implant cantypically have a thickness ranging from about 0.2 mm to about 2 mm, fromabout 0.8 mm to about 1.5 mm, or from about 0.3 mm to about 1.0 mm. Oneexample of a pellet or disc is illustrated in FIG. 1, which has adiameter of about 2 to 2.5 mm and a thickness of about 1.0-1.5 mm. Inone specific example, the implant can have rounded edges, hemispherical,or semi-circular shapes.

In yet other specific examples, the implant can be shaped as a rod.Where this is the case, the implant can typically have a diameterranging from about 0.05 mm to about 2 mm, from about 0.1 mm to about 1.0mm, or from about 0.2 mm to about 0.8 mm. Further, in some examples, therod-shaped implant can typically have a length ranging from about 0.5 mmto about 5 mm, from about 1.0 mm to about 3.0 mm, or from about 1.5 mmto about 2.5 mm.

Yet another aspect of the present invention provides a method oftreating an eye condition. It is noted that when discussing variousexamples and embodiments of the implantable devices, systems, andmethods described herein, each of these respective discussions can alsoapply to each of the other aspects of the present invention. Thus, forexample, when discussing the implantable device per se, this discussionis also relevant to the methods discussed herein, and vice versa.

With this in mind, in some specific examples, the method can includeinserting an intraocular active agent delivery device, as describedherein, into the lens capsule or ciliary sulcus of an eye to deliver anactive agent to the eye. In some examples, the intraocular active agentdelivery device can include an active agent homogenously combined with abiodegradable active agent matrix such that the entire delivery deviceis homogenous.

Further, in some examples, the delivery device can have a shape and sizeto provide a therapeutically effective amount of the active agent to theeye. Further still, in some examples, the delivery device can include abiodegradable active agent matrix that is formulated to providesustained release of a therapeutically effective amount of the activeduring a release period. Where the delivery device includes abiodegradable active agent matrix, the biodegradable active agent matrixcan be allowed to biodegrade to provide sustained release of the activeagent to the eye during a release period.

In some examples, the intraocular active agent delivery device canprovide an amount of the active agent to reduce retinal thickeningassociated with an ocular condition (e.g. cystoid macular edema) ascompared to retinal thickening without treatment. In some furtherexamples, sustained release of the amount of active agent can reduceretinal thickening associated with an ocular condition as compared toretinal thickening without treatment. Further, in some examples, for asubject in need thereof, treatment with the intraocular active agentdelivery device can reduce retinal thickness by at least 10 μm, at least20 μm, or more within 2 weeks or 1 week of insertion of the intraocularactive agent delivery device into the eye as compared to the retinalthickness in the eye without treatment.

In some examples, the method can include performing a cataract removalsurgery on the eye of the subject, further including removing anexisting lens from the eye of the subject, inserting an intraocular lensinto the eye of the subject, and placing the biodegradable active agentmatrix within the lens capsule. In some examples, the biodegradableactive agent matrix or implant can be associated with the intraocularlens. Where this is the case, the delivery device may be attached ordetached from an intraocular lens. The delivery device can be associatedby actual contact or sufficient proximity while allowing effectivediffusion of active agent to target areas of the eye. A biodegradablesystem can have substantial value in routine cataract surgery to provideshort-term/time-limited delivery of postoperative medicines whileminimizing or eliminating the need for eyedrop usage by the patient. Thelens that is removed can be the original natural lens of the eye, or itcan be a lens that was previously inserted into the eye as a result of aprior procedure.

Numerous methods of placing the device into the eye are contemplated.For example, in one aspect, the implant can be associated with theintraocular lens prior to inserting the intraocular lens into the eye.In such cases it can be necessary to configure the implant to complywith any requirements of the surgical procedure. For example, cataractsurgeries are often performed through a small incision. One standardsize incision is about 2.75 mm; although this device can be compatiblewith smaller or larger incision sizes as well. As such, the intraocularlens assembly can be shaped to allow insertion through this smallopening. Thus the active agent delivery device can also be configured tobe inserted with the intraocular lens assembly, e.g. by shape and/orchoice of resilient and flexible material for the implant. Additionally,the active agent delivery device can also be physically coupled ordecoupled to the intraocular lens assembly prior to insertion of theassembly into the eye. In another aspect, the implant can be positionedwithin the lens capsule, and optionally associated with the intraocularlens assembly, following insertion of the lens into the eye. Thecapsular bag can be readily reopened for a patient having prior cataractsurgery. Thus, the insertion of the delivery device can be performedimmediately prior to insertion of an intraocular lens or later in timeas a separate procedure.

EXAMPLES Example 1

A standard clear-corneal phacoemulsification with intraocular lens(Acrysof SA60AT; Alcon) implantation was performed on 35 rabbits. At thetime of each surgery, an intraocular device containing an active agentwas inserted into a lens capsule of each rabbit. The rabbits weredivided into 4 groups, depending on the active agent in the intraoculardevice. Devices were loaded with 5-15 mg of either Avastin, Timolol,Brimonidine, or Latanoprost. Each group was evaluated to determine theintraocular device and lens stability, capsular fibrosis, and healing ofcataract wounds and anterior segment. A subgroup of eyes was evaluatedweekly for 4 weeks for inflammation and harvested at 1 month forhistopathologic evaluation of capsular and CDR integrity.

Example 2

The surgery and setup as described in Example 1 was repeated, with theexception that aqueous and vitreous taps were performed biweekly andassayed for drug concentrations with HPLC and/or ELISA. In each druggroup, half of the eyes were harvested at one month and the other halfat two months. This was accomplished as follows: immediately aftersacrificing the rabbit and enucleating the eye, the eye was frozen inliquid nitrogen to prevent perturbation and redistribution of drug ineye tissues. The eye was then dissected into 3 parts (aqueous humor,vitreous and retina/choroid layer) to evaluate anatomic toxicity andtissue drug concentration. The intraocular device was retrieved andassessed for remaining drug amounts. The distribution profile of theintraocular device was compared with the conventional intravitrealinjection of 2.5 mg/0.1 cc Avastin® for direct comparison of thedifferent delivery methods.

At 2 and 4 months, eyes from the remaining subgroups of rabbits wereenucleated, fixed by 10% formalin, embedded in paraffin, step sectioned,stained by hematoxyline and eosin (H & E), and examined for histologicalchanges.

Example 3

Three intraocular devices were implanted into eyes of New Zealand whiterabbits under general anesthesia after lens extraction(phacoemulsification technique). Two of the devices were loaded withAvastin and one was loaded with the contrast agent Galbumin as acontrol. Proper intraocular device position was verified by MRI as wellas clinical examination.

The rabbits were sacrificed and the eyes are removed and assayed after 1week post implantation. Avastin was detected by ELISA in the retina andvitreous at concentrations of 24-48 mcg/mL, and was not present in thecontrol rabbit eye. FIG. 5 shows the amount of Avastin assayed perocular region at 1 week post implantation.

Example 4

To confirm that placement of implant in the capsular bag and deliversdrugs both to the front and back of the eye for short and long term,microparticles were prepared using PLGA [poly(d,l-lactide-co-glycolide),MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose (HPMC)and dexamethasone. Dexamethasone loaded PLGA microspheres were preparedusing standard oil-in-water (o/w) emulsion-solvent extraction method. Anamount of 160 mg PLGA was dissolved in 4 mL methylene chloride and 1 mLacetonitrile. An amount of 40 mg dexamethasone and 10 mg of HPMC wasdispersed in the PLGA solution by vortexing for 5 min. This organicphase was then emulsified in 20 mL of a 2% (w/v) PVA (MW 90 kDa)solution and homogenized. The resultant emulsion was poured into 200 mLof a 2.0% (w/v) PVA (MW 90 kDa) solution and stirred in an ice bath for6 min. The contents were stirred for 8 hr at room temperature toevaporate the dichloromethane and acetonitrile to form a turbidmicroparticulate suspension. The microparticles were separated bycentrifugation, washed twice, resuspended in deionized water, andfreeze-dried to obtain lyophilized particles. The preparedmicroparticles were characterized and pelleted using bench top pelletpress with 2 mm die set to form an implant.

These implants were sterilized, implanted in the capsular bag ofrabbit's eyes. Two dose groups were used (300 and 600 μg), two rabbitswere sacrificed from each of low and high dose group at 1, 2, 4, 6 weeksand various tissue samples (aqueous humor, vitreous humor, IOL,iris/ciliary body and retina/choroid) were collected and samples wereanalyzed by a validated LC/MS/MS method. Microspheres were in the rangeof 6±2 μM as confirmed by Zetasizer nano and SEM photomicrographs. Drugloading in the microparticles was >99% and the final yield was 60% (i.e.encapsulation efficiency). Drug loading was determined as percent drugloading=(weight of drug loaded/weight of microspheres)×100. Dose relatedpharmacokinetics with near zero order kinetics was observed in rabbitsup to 6 weeks. Further, dexamethasone flow was bidirectional from theendocapsular space into both the anterior and posterior chambers. Therewere also no cells or formation of fibrin in the anterior and posteriorchambers of the eye. Histological examinations revealed all the tissuesexamined were normal and showed no signs of inflammation.

All the study animals were acquainted to study room conditions once theyare out of quarantine and randomized. All the positive control group andimplantation groups underwent phacoemulsification and insertion of anintraocular lens (TOL) in both the eyes. Group III and IV received oneand two implants per eye respectively.

Group I: Normal control group; n=6

Group II: Phacoemulsification and inserting IOL; DXM drops (up to 4weeks with tapering) and antibiotic drops (up to 2 days); positivecontrol group; n=6

Group-III: Phacoemulsification and inserting IOL; BDI implant low dose(one implant per eye) and antibiotic drops up to 2 days (b.i.d.) aftersurgery; n=8

Group-IV: Phacoemulsification and inserting IOL; BDI implant high dose(two implants per eye) and antibiotic drops up to 2 days (b.i.d.) aftersurgery, n=8

Results of in vitro release kinetics are presented in FIG. 10. All thebatches exhibited biphasic release pattern with initial burst release onday-1 and thereafter slow and sustained release. The burst effect wasslightly higher with implants containing HPMC.

A total of 16 animals (32 eyes) received the implant. Dexamethasoneconcentrations are presented in FIG. 11 through FIG. 14. The implantsdegraded slowly over 4 weeks and by week 6 were completely disappeared.Therapeutic concentrations of DXM was found up to week 6 with minimalsystemic exposure (<40 ng/mL with high dose), whereas, withdexamethasone drops systemic exposure was higher (>150 ng/mL during week1). Mean PK parameters for BDI-2 implant and positive control group inaqueous humor, vitreous humor, retina/choroid, and iris/ciliary body areshown in Table 1 and 2.

TABLE 1 Pharmacokinetics in aqueous humor and vitreous humor Low dose:300 μg High dose: 600 μg Dexamethasone Drops Aqueous Vitreous AqueousVitreous Aqueous Vitreous Parameter humor humor humor humor humor humorC_(max (ng/mL)) 650 ± 109 892 ± 151 1570 ± 113  1379 ± 233 62 ± 24 3 ± 0T_(max (day)) 19 ± 8  28 ± 0  7 ± 0 28 ± 0 14 ± 0  16 ± 11AUC_(0-t (day*ng/mL)) 15231 ± 361  18317 ± 2435  28202 ± 3369  32933 ±4027 1023 ± 320  61 ± 5  C_(last (ng/mL)) 8 ± 3 2 ± 1 52 ± 18  85 ± 23 6± 2 2 ± 1

TABLE 2 Pharmacokinetics in retina/choroid and iris/ciliary body Lowdose: 300 μg High dose: 600 μg Dexamethasone Drops Retina/ Retina/Retina/ Parameter Choroid Iris/CB Choroid Iris/CB Choroid Iris/CBC_(max (μM)) 21 ± 4 35 ± 5  117 ± 40 209 ± 24  3 ± 1 3 ± 2 T_(max (day))14 ± 0 7 ± 0 23 ± 8 14 ± 0  14 ± 0  9 ± 4 AUC_(0-t (day*μM)) 455 ± 61759 ± 132  2226 ± 1105 3913 ± 685  48 ± 16 42 ± 27 C_(last (μM))  1.3 ±0.6 1.5 ± 0.5 12 ± 8 13 ± 10 0.2 ± 0.1 0.5 ± 0.3

Intraocular pressure was normal in all the groups. Further, there wereno signs of anterior or posterior chamber inflammation as assessed withSlit lamp biomicroscopy and confirmed by histological examination. Therewas a trend in increase in retinal thickness in animals treated withdexamethasone drops whereas, implants maintained retinal thickness.

The PLGA polymer degrades in to lactic and glycolic acid throughhydrolysis, then further degrades in to carbon dioxide and water beforeeliminating from the body. Implants did not migrate to the center toobstruct the visual field.

BDI-1 implant was manufactured by following partial solvent castingmethod with subsequent evaporation and removing the residual solvent bydrying the product under high vacuum for 3 days. Various implants wereprepared using PLGA [poly(d,l-lactide-co-glycolide), MW. 7000-17000,acid terminated], hydroxypropyl methyl cellulose (HPMC), croscarmellosesodium (cross linked sodium carboxymethylcellulose), hydroxypropylcellulose and dexamethasone in several different compositions.

The dried particles were directly pelleted using bench top pellet presswith a 2 mm die set to form an implant.

The selected BDI-1 implants (from in-vitro release studies, FIG. 7) weresterilized, implanted in the capsular bag of rabbit's eyes. Two implantswith different composition and dose were tested in-vivo in NZW rabbitsto establish pharmacokinetics. Two rabbits were sacrificed at 2, 6, 10,15 days and various tissue samples (aqueous humor, vitreous humor, IOL,iris/ciliary body and retina/choroid) were collected and samples wereanalyzed by a validated LC/MS/MS method. Pharmacokinetics with near zeroorder kinetics was observed in rabbits up to 15 days. Further,dexamethasone flow was bidirectional from the endocapsular space intoboth the anterior and posterior chambers. There were also no cells orformation of fibrin in the anterior and posterior chambers of the eye.Histological examinations revealed all the tissues examined were normaland showed no signs of inflammation.

Results of in vitro release kinetics are presented in FIG. 7. All thebatches exhibited smooth release pattern with initial burst release onday-1 and thereafter slow and sustained release. The burst effect wasslightly higher with implants containing HPMC.

A total of 8 animals (16 eyes) received the implant containing 120 μg ofDXM. DXM concentrations are presented in FIG. 8 FIG. 9. The implantseroded slowly over 10 days and reaching trough concentrations of DXM byday 15. The implants are degraded by 80% of its mass by day 15 andexpected to fully degrade by day 20. Therapeutic concentrations of DXMwas found up to day 15 with minimal systemic exposure (<23 ng/mL),whereas, with dexamethasone drops systemic exposure was higher (>150ng/mL during week 1, in-house data).

Example 5

A number of biodegradable implants were prepared with PLGA,croscarmellose sodium, and dexamethasone in accordance with Table 3below.

TABLE 3 Effect of CrosCarmellose on Drug Release Rate PLGACroscarmellose Dexamethasone Formulation (wt %) (wt %) (wt %) Series 185 0 15 Series 2 84 1 15 Series 3 83.5 1.5 15 Series 4 83 2 15 Series 582.5 2.5 15 Series 6 82 3 15 Series 7 80 5 15 Series 8 77.5 7.5 15

Drug release profiles for each of the listed formulations were obtainedusing an in-vitro drug release model. Individual drug release profilesare presented in FIG. 10. As illustrated in FIG. 10, increasing amountsof croscarmellose can increase the drug release rate from thebiodegradable implant as compared to a biodegradable implant preparedwith only PLGA.

Example 6

Two biodegradable dexamethasone implants (BDI) were prepared usingdifferent formulations including PLGA, croscarmellose, anddexamethasone. The first BDI was configured to deliver 200 mcgdexamethasone over a period of two weeks. The second BDI was configuredto deliver 300 mcg dexamethasone over a period of six weeks. The drugrelease profiles were evaluating using an in-vitro drug release model.The release profile for the first and second BDIs are illustrated inFIGS. 11 and 12, respectively.

Further, these implants were sterilized and implanted in the capsularbag of rabbit's eyes. The implants degraded slowly over a number ofweeks until they completely disappeared. Mean PK parameters for thefirst BDI implant and positive control group in aqueous humor, vitreoushumor, retina/choroid, and iris/ciliary body are shown in Tables 4 and5.

TABLE 4 Pharmacokinetics in aqueous humor and vitreous humor for firstBDI Dexamethasone BDI: 200 μg Drops Aqueous Vitreous Aqueous VitreousParameter humor humor humor humor C_(max (ng/mL)) 259 ± 20 296 ± 32 92 ±12 15 ± 4 T_(max (day))  6 ± 0 10 ± 0 2 ± 0  3 ± 2 AUC_(0-t (day*ng/mL))2365 ± 182 2769 ± 276 517 ± 43  104 ± 42 C_(last (ng/mL))  52 ± 20  34 ±14 23 ± 6   1 ± 1

TABLE 5 Pharmacokinetics in retina/choroid and iris/ciliary body forfirst BDI Dexamethasone BDI: 200 μg Drops Retina/ Retina/ ParameterChoroid Iris/CB Choroid Iris/CB C_(max (μM)) 133 ± 12  38 ± 6 3.3 ± 0.82.2 ± 0.5 T_(max (day)) 9 ± 2  6 ± 4 6 ± 0 3 ± 2 AUC_(0-t (day*μM)) 1264± 66  312 ± 46 23 ± 4  19 ± 8  C_(last (μM)) 26 ± 10 16 ± 6 0.9 ± 0.20.6 ± 0.2

Dexamethasone concentration profiles for each of the ocular regions arepresented in FIG. 13 through FIG. 16. Further, the retinal thicknessesfor each of the test subjects were measured over time and compared toretinal thicknesses for test subjects treated with a topical formulationand control subjects with normal retinal thickness. These results aredepicted in FIG. 17. As illustrated in FIG. 17, a therapeuticallyeffective dose can reduce retinal thickening associated with an ocularcondition as compared to retinal thickening without treatment or ascompared to treatment with a topical formulation.

Mean PK parameters for the second BDI implant and positive control groupin aqueous humor, vitreous humor, retina/choroid, and iris/ciliary bodyare shown in Tables 6 and 7.

TABLE 6 Pharmacokinetics in aqueous humor and vitreous humor for secondBDI Dexamethasone BDI: 300 μg Drops Aqueous Vitreous Aqueous VitreousParameter humor humor humor humor C_(max (ng/mL)) 314 ± 55  86 ± 10  72± 19 2.2 ± 0.3 T_(max (day)) 28 ± 0  21 ± 12  7 ± 0 9 ± 4AUC_(0-t (day*ng/mL)) 8377 ± 1055 2329 ± 219  1533 ± 325 68 ± 5 C_(last (ng/mL)) 232 ± 29  35 ± 8  17 ± 8 2 ± 1

TABLE 7 Pharmacokinetics in retina/choroid and iris/ciliary body forsecond BDI Dexamethasone BDI: 300 μg Drops Retina/ Retina/ ParameterChoroid Iris/CB Choroid Iris/CB C_(max (μM)) 6.4 ± 0.7 1.1 ± 0.2 0.13 ±0.06 0.06 ± 0.01 T_(max (day)) 7 ± 0 14 ± 0  14 ± 12 23 ± 8 AUC_(0-t (day*μM)) 99 ± 19 28 ± 6  2.3 ± 0.7 1.2 ± 0.2 C_(last (μM)) 1.7± 0.2 0.8 ± 0.2 0.11 ± 0.06 0.06 ± 0.01

Dexamethasone concentration profiles for each of the ocular regions arepresented in FIG. 18 through FIG. 21. Further, the retinal thicknessesfor each of the test subjects were measured over time and compared toretinal thicknesses for test subjects treated with a topical formulationand control subjects with normal retinal thickness. These results aredepicted in FIG. 22. As illustrated in FIG. 22, a therapeuticallyeffective dose can reduce retinal thickening associated with an ocularcondition as compared to retinal thickening without treatment or ascompared to treatment with a topical formulation.

Example 7

A number of biodegradable implants were prepared with PLGA,croscarmellose sodium, and dexamethasone in accordance with Table 8below.

TABLE 8 Effect of CrosCarmellose on Drug Release Rate PLGACroscarmellose Dexamethasone Formulation (wt %) (wt %) (wt %) Series 966 4 30 Series 10 64 6 30 Series 11 62 8 30 Series 12 67.5 10 22.5Series 13 65 12.5 22.5 Series 14 62.5 15 22.5 Series 15 60 17.5 22.5Series 16 57.5 20 22.5 Series 17 70 20 10 Series 18 79 6 15 Series 19 787 15 Series 20 85 0 15 Series 21 84 1 15 Series 22 83 1.5 15 Series 2383 2 15 Series 24 82.5 3 15 Series 25 81 4 15 Series 26 80 4.5 15 Series27 80 5 15 Series 28 77.5 7.5 15

Drug release profiles for each of the listed formulations were obtainedusing an in-vitro drug release model. Notably, lower croscarmellosepercentages increase duration of dexamethasone release. We found that 0to 10% of croscarmellose ranges afforded a 6 week release profile, while0 to 5% further increased release up to 12 months. In contrast, 15-25%croscarmellose ranges yielded a shorter 2 week release profile, although20 to 25% was also useful.

It should be understood that the above-described arrangements are onlyillustrative of application of the principles of the present invention.Numerous modifications and alternative arrangements may be devised bythose skilled in the art without departing from the spirit and scope ofthe present invention. Thus, while the present invention has beendescribed above with particularity and detail in connection with what ispresently deemed to be the most practical and preferred embodiments ofthe invention, it will be apparent to those of ordinary skill in the artthat numerous modifications, including, but not limited to, variationsin size, materials, shape, form, function and manner of operation,assembly and use may be made without departing from the principles andconcepts set forth herein.

What is claimed is:
 1. An intraocular active agent delivery device,comprising: an active agent homogenously combined with a biodegradableactive agent matrix such that the entire delivery device is homogenous,said homogenous delivery device having a shape and size to fit within alens capsule or ciliary sulcus of an eye and provide a therapeuticallyeffective amount of the active agent to the eye, said active agentincluding dexamethasone, and said biodegradable active agent matrixbeing formulated to provide sustained release of the therapeuticallyeffective amount of the active agent during a release period.
 2. Thedevice of claim 1, wherein the active agent is present in thebiodegradable active agent matrix in an amount from about 5 wt % toabout 25 wt %.
 3. The device of claim 1, wherein the release period isfrom about 2 weeks to about 8 weeks.
 4. The device of claim 1, whereinthe sustained release of the therapeutically effective amount of theactive agent is provided to both the anterior and posterior segments ofthe eye.
 5. The device of claim 1, wherein the biodegradable activeagent matrix comprises at least one of poly(lactic-co-glycolide),polylactic-polyglycolic acid block copolymers (PLGA), hydroxypropylmethyl cellulose (HPMC), hydroxyl methyl cellulose,polyglycolide-polyvinyl alcohol, hydroxypropylcellulose, sodiumcarboxymethylcellulose, polylactic acid (PLA), polyglycolic acid (PGA)polyglycolic acid-polyvinyl alcohol block copolymers (PGA/PVA),hydroxypropylmethylcellulose (HPMC), polycaprolactone (PCL), andpolycaprolactone-polyethylene glycol block copolymers.
 6. The device ofclaim 1, wherein the biodegradable active agent matrix comprisespoly(lactic-co-glycolide) having a copolymer ratio from about 60/40 toabout 40/60.
 7. The device of claim 1, wherein the biodegradable activeagent matrix further comprises a disintegrant.
 8. The device of claim 7,wherein the disintegrant is croscarmellose, or a salt thereof.
 9. Thedevice of claim 1, wherein the device is in the form of a suspension ordispersion of the active agent within a biodegradable polymer matrixprecursor, the biodegradable polymer matrix precursor forming thebiodegradable active agent matrix in situ.
 10. The device of claim 1,wherein the delivery device has a total mass of 0.2 mg to 4 mg.
 11. Thedevice of claim 1, wherein the biodegradable active agent matrix isshaped as a crescent, disc, rod, or pellet.
 12. The device of claim 11,wherein the disc or pellet has a diameter ranging from about 0.4 mm toabout 3 mm and a thickness ranging from about 0.2 mm to about 2 mm. 13.The device of claim 11, wherein the biodegradable active agent matrix isshaped as a rod.
 14. The device of claim 13, wherein the rod has adiameter ranging from about 0.05 mm to about 2 mm and a length rangingfrom about 0.5 mm to about 5 mm.
 15. The device of claim 1, wherein thedelivery device releases on average from 1 mcg to 12 mcg per day of theactive agent during the release period.
 16. The device of claim 1,wherein the delivery device releases from 100 mcg to 400 mcg of theactive agent during the release period.
 17. A method of treating an eyecondition, comprising: inserting an intraocular active agent deliverydevice into the lens capsule or ciliary sulcus of an eye, saidintraocular drug delivery device including an active agent homogenouslycombined with a biodegradable active agent matrix such that the entiredelivery device is homogenous, said homogenous delivery device having ashape and size to provide a therapeutically effective amount of theactive agent to the eye, said active agent including dexamethasone, andsaid biodegradable active agent matrix being formulated to providesustained release of a therapeutically effective amount of the activeagent during a release period; and allowing the biodegradable activeagent matrix to biodegrade to provide sustained release of thetherapeutically effective amount of the active agent to the eye duringthe release period.
 18. The method of claim 17, wherein the inserting isperformed during a cataract surgery.
 19. The method of claim 17, whereinthe inserting is performed after a cataract surgery to treatpost-operative cataract surgical inflammation.
 20. The method of claim17, wherein the eye condition is uveitis.
 21. The method of claim 17,wherein the release period is from 2 weeks to 8 weeks.
 22. The method ofclaim 17, wherein the sustained release of the active agent providesfrom 100 mcg to 400 mcg of the active agent during the release period.23. The method of claim 17, wherein the sustained release of the activeagent provides on average from 1 mcg to 12 mcg per day of the activeagent during the release period.
 24. The method of claim 17, wherein thesustained release of the active agent reduces retinal thickeningassociated with the ocular condition as compared to retinal thickeningwithout treatment.
 25. The method of claim 24, wherein retinal thicknessis reduced by at least 10 μm within a period of 2 weeks after insertingthe intraocular active agent delivery device as compared to retinalthickness without treatment.